WO2005036502A2 - Modeles de colonne vertebrale tridimensionnels in vitro et procedes pour analyser la repartition d'une substance dans ces modeles - Google Patents

Modeles de colonne vertebrale tridimensionnels in vitro et procedes pour analyser la repartition d'une substance dans ces modeles Download PDF

Info

Publication number
WO2005036502A2
WO2005036502A2 PCT/US2004/032642 US2004032642W WO2005036502A2 WO 2005036502 A2 WO2005036502 A2 WO 2005036502A2 US 2004032642 W US2004032642 W US 2004032642W WO 2005036502 A2 WO2005036502 A2 WO 2005036502A2
Authority
WO
WIPO (PCT)
Prior art keywords
passageway
fluid
model
model apparatus
cord structure
Prior art date
Application number
PCT/US2004/032642
Other languages
English (en)
Other versions
WO2005036502A3 (fr
Inventor
Kenneth T. Heruth
Mark S. Lent
Michael Hegland
Original Assignee
Medtronic, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Medtronic, Inc. filed Critical Medtronic, Inc.
Publication of WO2005036502A2 publication Critical patent/WO2005036502A2/fr
Publication of WO2005036502A3 publication Critical patent/WO2005036502A3/fr

Links

Classifications

    • G—PHYSICS
    • G09—EDUCATION; CRYPTOGRAPHY; DISPLAY; ADVERTISING; SEALS
    • G09B—EDUCATIONAL OR DEMONSTRATION APPLIANCES; APPLIANCES FOR TEACHING, OR COMMUNICATING WITH, THE BLIND, DEAF OR MUTE; MODELS; PLANETARIA; GLOBES; MAPS; DIAGRAMS
    • G09B23/00—Models for scientific, medical, or mathematical purposes, e.g. full-sized devices for demonstration purposes
    • G09B23/28—Models for scientific, medical, or mathematical purposes, e.g. full-sized devices for demonstration purposes for medicine
    • G09B23/30—Anatomical models
    • G09B23/34—Anatomical models with removable parts
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y50/00—Data acquisition or data processing for additive manufacturing
    • G—PHYSICS
    • G09—EDUCATION; CRYPTOGRAPHY; DISPLAY; ADVERTISING; SEALS
    • G09B—EDUCATIONAL OR DEMONSTRATION APPLIANCES; APPLIANCES FOR TEACHING, OR COMMUNICATING WITH, THE BLIND, DEAF OR MUTE; MODELS; PLANETARIA; GLOBES; MAPS; DIAGRAMS
    • G09B23/00—Models for scientific, medical, or mathematical purposes, e.g. full-sized devices for demonstration purposes
    • G09B23/28—Models for scientific, medical, or mathematical purposes, e.g. full-sized devices for demonstration purposes for medicine
    • G09B23/30—Anatomical models
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y80/00—Products made by additive manufacturing

Definitions

  • the present invention relates generally to the field of spinal cord research and, more particularly, to three dimensional in-vitro human spinal models and methods of simulating and analyzing substance, e.g., drug, distribution patterns therein.
  • substance e.g., drug, distribution patterns therein.
  • BACKGROUND Self assessment of therapeutic results from patients with implanted drug delivery systems for pain and spasticity therapy indicate that efficacy varies from poor to excellent. While there are a number of factors that may contribute to this variation, at least some of this disparity may be due to variability in the amount of drug that actually reaches the intended pain receptors. Stated alternatively, when the delivered drugs reach the intended receptors, it is believed that more effective therapy results.
  • therapeutic drugs When the delivered drugs are unable to reach the intended receptors, or are otherwise substantially diluted by the time they reach the intended receptors, therapeutic effects may be diminished. Further aggravating this problem is the fact that drugs that do not reach the desired receptors may migrate to yet other receptors, potentially resulting in unintended and undesirable side effects. Such side effects may necessitate a reduction in the overall drug dosage that the patient may safely tolerate.
  • therapeutic drugs are often infused, or otherwise delivered, into cerebrospinal fluid (CSF) contained within an intrathecal space surrounding the spinal cord. The drug may then distribute through the CSF, whereby at least some of the drug is intended to reach the target receptors. While effective, distribution of drugs through CSF is complex and is not well understood.
  • drug distribution mechanisms through CSF may include: diffusion through the CSF; diffusion into the spinal cord and epidural space, then diffusion through the tissues; natural CSF convection (CSF convection may result from production and uptake processes, arterial expansion from cardiac cycle, tissue displacement during the respiratory cycle, tissue displacement during body motion, etc.); mixing of the drug in CSF due to movement around spinal structures; and buoyancy due to differences in density.
  • CSF convection may result from production and uptake processes, arterial expansion from cardiac cycle, tissue displacement during the respiratory cycle, tissue displacement during body motion, etc.
  • mixing of the drug in CSF due to movement around spinal structures and buoyancy due to differences in density.
  • CSF samples are generally only taken below the cauda equina or in the cisterna magna to avoid damaging the spinal cord with the sampling needle.
  • drug presence at receptors located at specific locations along the spinal cord is difficult to quantify.
  • drugs introduced into CSF are not easily imaged via non- invasive methods. Rather, as drug concentration in CSF is low, a marker or contrast agent is generally required for accurate detection.
  • markers pose a potential risk of neurotoxicity.
  • 11 lln-DTPA is approved and labeled for use in the central nervous system (CNS) by the U.S. Food and Drug Administration.
  • 11 lln-DTPA may be detected with nuclear imaging cameras, it is also much heavier than many neurological drugs and thus may not distribute within CSF in the same manner. Still further, while small and large animal models have been used to study drug distribution within the spine, such animals do not have a spinal anatomy that is similar to humans, primarily because these animals do not walk, stand, and sit upright. Thus, such animal studies are not believed to provide an accurate prediction of drug distribution in humans.
  • the present invention provides an in-vitro spinal model that permits the study and analysis of how a substance may be distributed along a human spinal canal.
  • the model may be used to characterize distribution patterns, potentially allowing more effective drug therapy.
  • a three-dimensional in-vitro model apparatus of a human spine is provided.
  • the model apparatus may include a model body having a column portion, where the column portion defines a curved passageway in the shape of a human spinal canal.
  • a cord structure is also included and located within the passageway of the column portion. The cord structure is securable within the passageway such that an annular region is formed between a wall of the passageway and the cord structure.
  • the model apparatus may optionally include one or more of the following features: a fluid occupying the annular region; a variation in cross-sectional area and cross-sectional shape of one or both of the passageway and the cord structure over their respective longitudinal lengths; at least one root element extending between the cord structure and the wall of the passageway; fin members extending between the cord structure and the wall of the passageway, the fin members operable to partition the annular region into two or more longitudinal chambers; a pump assembly operatively coupled to the passageway; an oscillatory flow apparatus operable to create an oscillating flow of the fluid through the annular region; and tube elements extending along a portion of the length of the cord structure, each tube element having a first end coupled to the cord structure.
  • a method of characterizing a distribution of a substance in a human spinal column may include introducing a second fluid comprising the substance into a first fluid, where the first fluid is located within an annular region of a spinal model.
  • the spinal model may include a model body having a column portion, where the column portion defines a curved passageway in the shape of a human spinal canal.
  • the model may also include a cord structure located within the passageway of the column portion, wherein the cord structure is securable within the passageway such that the annular region is formed between a wall of the passageway and the cord structure.
  • the method may also include detecting a concentration of the substance within the first fluid at one or more locations along the passageway.
  • the method may optionally include: visually monitoring the distribution of the substance within the first fluid through a transparent portion of the column portion; and circulating the first fluid within the annular region.
  • Figure 1 illustrates a side elevation view of an in-vitro spinal model apparatus in accordance with one embodiment of the invention
  • Figure 2 is an exploded view of the spinal model apparatus of Figure 1, wherein a cord structure is shown in conjunction with a model body defining a column portion having a passageway therein
  • Figure 3 is a side elevation view of the cord structure of Figure 2
  • Figure 4 is a front elevation view of the cord structure of Figure 2
  • Figure 5 is a perspective view of a portion of the cord structure of Figure 2
  • Figure 6 is a cutaway, perspective view of a portion of the cord structure of Figure 2 as it may be positioned within the passageway
  • Figure 7 is a diagrammatic view of an in-vitro spinal model apparatus in accordance with one embodiment of the invention
  • Figure 8 is a partial cross section of the apparatus of Figure 7 taken along lines 8-8 of Figure 7 (view rotated 90 degrees for clarity)
  • Figure 9 is a diagrammatic view of an in-vitro spinal model apparatus in accordance with one embodiment of the invention
  • the present invention is generally directed to in-vitro spinal models. More specifically, the present invention is directed to spinal model apparatus and methods for visualizing and analyzing distribution of substances, e.g., drugs, delivered within a spinal column via implantable catheters or other techniques now known or later developed.
  • substances e.g., drugs
  • FIG. 1 illustrates a three-dimensional in-vitro spinal model apparatus 100 (also referred to herein as "model") in accordance with one embodiment of the invention.
  • the apparatus 100 may include a model body 200 including a column portion that surrounds and defines a substantially enclosed curved passageway 202 operable to receive therein a cord structure 300.
  • the passageway 202 and cord structure 300 substantially mimic, in size, shape, and structure, the corresponding spinal canal and spinal cord of a spine 50 of a standing adult human.
  • Figure 1 illustrates the vertebrae sections of a typical human spine 50.
  • the vertebrae are identified according to their particular location along the spinal column.
  • the uppermost vertebrae are the cervical vertebrae 52, which include seven vertebrae commonly identified as Cl - C7 (in descending order in Figure 1).
  • the thoracic vertebrae 54 which include twelve vertebrae identified as TI - T12 (in descending order).
  • the lumbar vertebrae 56 which include five vertebrae identified as LI - L5 (in descending order).
  • the sacral vertebrae 58 At the lower end of the spinal column 50 is the sacral vertebrae 58.
  • the apparatus 100 may include indicia that identify one or more of these vertebral locations, e.g., TI - T12, on the model body 200.
  • Figure 2 is an exploded view of the apparatus 100.
  • the model body 200 may be formed from mating halves 204a and 204b that are substantially mirror images of one another.
  • Each half 204a, 204b may have formed therein a channel 202a, 202b, respectively, such that when the halves are assembled, the channels 202a, 202b combine to form the passageway 202.
  • the halves 204a and 204b may be attached to one another via most any technique.
  • fasteners 206 (only one shown in Figure 2) may pass through the body half 204a and thread into the half 204b or, alternatively, pass through both halves, 204a, 204b and be secured with a nut.
  • the body halves 204a, 204b may be made from most any material.
  • the halves are made from transparent acrylic plates each approximately 92 centimeters (cm) high, 20 cm wide, and 3.5 cm thick.
  • the use of acrylic provides numerous advantages including, for example, simplified machining of the channels 202a, 202b, and generally unimpeded visibility of the entire passageway 202 and cord structure 300 during use.
  • the halves 204a, 204b may incorporate a sealing member, e.g., a gasket or an O-ring, that surrounds the passageway 202 so that fluids within the passageway may be contained therein.
  • a sealing member e.g., a gasket or an O-ring
  • the cord structure 300 may include a longitudinal cord portion 302 to simulate the human spinal cord. It may also include other portions, e.g., connecting elements, that permit the cord structure to be anchored relative to the body halves 204a, 204b.
  • the cord structure 300 may include a dorsal fin member 304 extending along the longitudinal length of the posterior side of the cord portion 302 and spanning across the annular region. The fin member 304 may be retained or trapped between the halves 204a and 204b, e.g., in a groove 208.
  • the dorsal fin member 304 as further described below, may generally anatomically mimic the membraneous septum posticum of the human spine.
  • the dorsal fin member 304 provides a wall dividing the posterior left and right sides of the passageway 202.
  • other connecting elements e.g., transverse tabs 306 and lateral fin members 312.
  • the tabs 306 are operable to be received within openings 210 in the model body 200, while the lateral fin members 312 may extend to and, in some embodiments, through, an inner wall of the passageway 202.
  • the transverse tabs 306 and lateral fin members 312 are designed to simulate other aspects of the human spine.
  • the human spine area was digitized using information obtained from The Visible Human Project (VHP) of the National Library of Medicine, Bethesda, MD, USA. Due to resolution limitations in the cross sections obtained, many tissue boundaries were too faint to permit clear visual separation within the images. To rectify this problem, anatomy textbooks were utilized to manually resolve the expanded images based upon where tissue boundaries were most likely located. During this process, fine structures that could not be discerned, e.g., nerve roots, dentate ligament, and septum posticum, were also added to the images. These images were manually entered into a computer aided design (CAD) model, after which the cross sections were combined into a three-dimensional CAD model.
  • CAD computer aided design
  • the subject of the VHP had some common irregularities in his spinal anatomy, e.g., minor scoliosis, asymmetric spinal cord and spinal canal, and a spinal cord which was off-center within the spinal canal. While these irregularities are not unusual, they are also not consistent between individuals. These irregularities may result in variations in fluids flowing through the spinal canal and, as a result, potentially affect the mixing of substances, e.g., drugs, within the canal. Thus, for simplicity, the spinal model was modified from the VHP images to be generally symmetrical.
  • the three- dimensional channels 202a, 202b were then milled into each half 204a, 204b, respectively.
  • the openings 210 were also machined to receive the tabs 306 ("nerve root bundles") of the cord structure 300 as further described below.
  • the combined channels 202a, 202b yielded the passageway 202, which corresponds to the intrathecal space in the spinal canal.
  • the CAD model was also used to create the three-dimensional model of the spinal cord structure 300 using stereolithography (SLA) techniques. Composite images of the cord structure 300 are illustrated in Figures 3-6, while representative cross sections are illustrated in Figures 8 and 10A-10D.
  • the cord structure 300 may be made in separate pieces, e.g., three pieces, and subsequently joined.
  • Figures 3 and 4 illustrate, respectively, a side elevation view and a front elevation view of the cord structure 300, whiles Figures 5 and 6 illustrate perspective views of the cord structure (with Figure 6 being a cut-away view).
  • the cord structure 300 may include the cord portion 302 (anatomically corresponding to the spinal cord) and, in some cord structure embodiments, dorsal root elements 308 (see Figures 5 and 6) and ventral root elements 310 (corresponding to dorsal and ventral nerve roots); and two lateral fin members 312 (corresponding to dentate ligaments).
  • the root elements 308 and 310 may converge on each side of the cord structure 300 to form the transverse tabs 306.
  • the transverse tabs 306 generally anatomically correspond to nerve root bundles that gather on each side of the spinal cord before exiting the spinal canal. As mentioned above, the tabs 306 may engage openings 210 in the model body 200 (see Figure 2).
  • FIG. 1 illustrates assembly of the spinal model apparatus 100 in accordance with one embodiment of the invention.
  • the cord structure 300 may be placed into the channel 202a of half 204a and the tabs 306 located in corresponding openings 210 of the half 204a.
  • the tabs 306 may deform slightly so that they form a relatively tight, waterproof seal with the openings 210.
  • the dorsal fin member 304 may locate in the receiving slot 208.
  • the opposing half 204b may then be coupled to the half 204a such that the channels 202b and 202a align.
  • the tabs 306 proximate the half 204b may then be engaged with the corresponding openings 210.
  • FIG 7 illustrates the model apparatus 100 as it may be configured for testing in accordance with one embodiment of the invention. For clarity, some features of the apparatus, e.g., some features of the cord structure 300, are not illustrated in Figure 7.
  • Figure 8 illustrates a detailed cross sectional view of the passageway 202 and cord structure 300 taken along lines 8-8 (level T10) of Figure 7. In Figure 8, the two halves 204a, 204b are shown assembled with the cord structure 300 captured between within the passageway 202.
  • Connecting elements including the dorsal fin member 304 (septum posticum), dorsal and ventral root elements 308, 310, transverse tabs 306 (nerve bundles), and lateral fin members 312 (dentate ligaments) are clearly identifiable within this cross sectional view. Also evident in this view is the partitioning of the resulting annular region between the cord member 300 and the walls of the passageway 202. In particular, the dorsal fin member 304 and lateral fin members 312 partition the passageway into three longitudinal chambers: an anterior chamber 212; a left posterior chamber 214; and a right posterior chamber 216. At some vertebral locations, the cord portion 302 may come close to, or even contact, a portion of the walls of the passageway 202.
  • FIG. 7 illustrates the apparatus 100 having other optional components.
  • the apparatus 100 may be configured as a table-top unit and thus include a base 102 and/or a base gusset 104 for support.
  • indicia 106 indicating the vertebral level e.g., Cl . . . C5, TI . . . T12, etc.
  • the vertebral level may be provided, as described above, at the respective locations on one or both sides of the body 200.
  • the passageway 202 may be filled with a fluid 108 having properties that simulate those of CSF. While CSF is composed primarily of saline, it also includes a variety of other substances, e.g., proteins, in solution. However, these other substances are not believed to have a major effect on fluid mechanics or mixing. Accordingly, in some embodiments, the passageway 202 may be filled with a saline solution to simulate CSF. In one embodiment, the saline solution may include about 0.9% sodium chloride. However, other solutions are certainly possible without departing from the scope of the invention. Magnetic resonance imaging (MRI) has indicated that spinal CSF oscillates in synchrony with the cardiac cycle. To simulate this oscillating flow, an oscillatory flow apparatus may be provided.
  • MRI Magnetic resonance imaging
  • the oscillatory flow apparatus may include a hydraulic cylinder 110 filled with saline (or other fluid) and connected to the passageway 202, e.g., at a port 112.
  • the cylinder 110 may be coupled to a small pneumatic cylinder 114 operable to cycle at about 1 Hertz (Hz) to simulate the cardiac cycle.
  • Amplitude may be adjustable so that the velocity of the fluid 108 does not exceed about 3 centimeters/second, a value accepted as typical in human physiology (see, e.g., On the Pulsatile Nature of Intracranial and Spinal CSF Circulation Demonstrated by MR Imaging, Greitz et al., Acta Radilologica 34 (1993) 321; Fourier Analysis of Cerebrospinal Fluid Flow Velocities: MR Imaging Study, Thomsen et al., Radiology 177 (1990) 659; and Flow Dynamics ofCerebrospinal Fluid: Assessment with Phase-Contrast Velocity MR Imaging Performed with Retrospective Cardiac Gating, Nitz et al., Radiology 183 (1992) 395).
  • the oscillation amplitude may be generally constant at all vertebral levels.
  • the pneumatic cylinder 114 may, in one embodiment, be controlled by a servovalve 116 coupled to a closed-loop controller, e.g., a computer 118.
  • a transducer (not shown) may provide feedback on one or more parameters, e.g., fluid velocity in the passageway 202, and adjust the cylinder 114 accordingly.
  • the cylinder 114 may include a flow control valve 120 calibrated to provide the desired flow rate, and a timer 121 operable to turn the valve 120 on and off at the desired interval.
  • the apparatus 100 may also include a mechanism to provide a substantially constant flow of CSF through the passageway 202.
  • Some anatomy textbooks report that such a continuous flow of CSF may enter the spinal canal on the dorsal side of the cord from the brain ventricles. The CSF is believed to travel downwardly along the dorsal side of the cord to the sacrum, where it then returns upwardly along the ventral side of the cord to the cisterna magna (for further discussion, see Spinal Descent ofCerebrospinal Fluid in Man, Di Chiro et al, Neurology 26 (1976) 1-8).
  • a continuous flow pump assembly e.g., peristaltic pump 122
  • the pump 122 draws fluid 108 from the anterior chamber 212 (see Figure 8) of the passageway 202 via a first connection 124. The flow may then be divided and returned to the left posterior chamber 214 and the right posterior chamber 216 of the passageway 202 via connections 126 and 128, respectively.
  • the pump 122 like the actuator 110, may be disabled to determine the distribution effects of both continuous and oscillatory flow rates.
  • the apparatus 100 may also optionally include a camera 130 to permit visual observation of drug distribution within the passageway 202.
  • the camera 130 may provide various visualization modes (e.g., still, video, time-lapse) to capture various fluid characteristics by visualizing a marker within an infused substance.
  • a drug (or other substance) may be infused or otherwise introduced into the passageway 202 via a catheter 132 (only partially shown in Figure 7).
  • One or both of the halves 204a, 204b may include a port, e.g., catheter port 218, that permits catheter entry into the passageway 202 in an anatomically realistic location.
  • the tip of the catheter 132 may be routed up the passageway 202 to the desired vertebral location, e.g., T10, and the catheter secured in place.
  • the catheter 132 may be coupled to an implantable infusion pump/programmer 220 or, alternatively, may receive the drug via other known methods, e.g., a syringe or a syringe pump (not shown).
  • Other embodiments may utilize spinal catheters such as the model 8703 W or model 8731 produced by Medtronic Corp. of Fridley, Minnesota, USA. .
  • any solution of substance may be introduced into the passageway 202, e.g., via the catheter port 218, in most any manner.
  • a solution including a substance could be introduced by bolus injection, continuous infusion, pulsatile infusion, and the like.
  • compositions of the solution may be modified to determine the effect of the modification on distribution of the substance in the passageway 202.
  • One or more of the camera 130, peristaltic pump 122, actuator 110, and other data collection and control devices may optionally be coupled to the computer 118 to provide automation of various test functions.
  • Figures 7 and 8 also diagrammatically illustrate sample taking devices, e.g., test probes 222 (only one probe illustrated in Figure 1), that may be located at sampling ports 221 (see Figure 8) proximate at least one vertebral location along the passageway 202.
  • the probes 222 may assist with detecting the presence and concentration of an infused drug within the passageway 202. While a variety of probes may be used without departing from the scope of the invention, the embodiment of Figures 7 and 8 may utilize what are referred to in the art as microdialysis probes.
  • Microdialysis is a technique for monitoring the chemistry of extracellular space in living tissue by functionally simulating a capillary. When a solution is passed through a microdialysis probe, the solution may equilibrate with the surrounding extracellular tissue fluid. The fluid sample gathered by the microdialysis probe will then contain representative proportions of the molecules present in the extracellular tissue's fluid.
  • the contents of the microdialysis probe may then be analyzed using various techniques, e.g., High Performance Liquid Chromatography (HPLC).
  • HPLC High Performance Liquid Chromatography
  • the microdialysis probe 222 utilized in some embodiments of the present invention is diagrammatically illustrated in Figure 9.
  • the probe is constructed with a tubular outer membrane 224 and a concentric inner tube 226. Fluid may enter the probe 222 at a proximal end 228 of the inner tube 226 and flow towards a distal end 230 as represented by arrows 231. The fluid may exit the inner tube 226 at or near the distal end 230 and enter the annular space between the inner tube 226 and the outer dialysis membrane 224.
  • FIG. 7 and 8 also illustrate a collection vial 234 (only one illustrated) that may be coupled via tubing 236 to each of the probes 222 to collect the microdialysis samples for subsequent analysis.
  • a collection vial 234 (only one illustrated) that may be coupled via tubing 236 to each of the probes 222 to collect the microdialysis samples for subsequent analysis.
  • three probes 222 were coupled to the apparatus 100 at each desired vertebral level. For instance, one vertebral level that was sampled was T10 shown in Figure 8.
  • probes 222 may be located to sample fluid from the anterior chamber 212, the left posterior chamber 214, and the right posterior chamber 216.
  • a similar probe configuration may be present at each vertebral level of interest.
  • Figures 10A-10D illustrate other exemplary partial cross sections of the model apparatus 100 as taken along the corresponding lines indicated in Figure 7 (note that, for simplicity, no probes 222 are illustrated in these views but, nevertheless, may be included at these vertebral levels in the same or different configuration as shown with respect to Figure 8).
  • the halves 204a, 204b and the cord structure 300 are clearly evident in these views, as are the transverse tabs 306 and dorsal fin member 304.
  • the varying relative dimensions, e.g., cross sectional shape and area, of the cord structure 300 and the passageway 202 are also evident over their respective longitudinal lengths in these views. As these cross-sections indicate, the model apparatus 100 may also simulate the more vertical positioning of the root elements 308 and 310 at the lower vertebral levels.
  • the apparatus 100 was configured as shown in Figure 7 and in accordance with the parameters shown in Table I.
  • the catheter 132 was inserted into the lumen 218 until the catheter tip was located on the right anterior side at or near vertebral level T10 (see Figure 7).
  • the passageway 202 was then filled with fluid 108 and the passageway, cylinder 110, and pump 122 were purged of air.
  • the apparatus 100 was then placed into a temperature control apparatus, e.g., a walk-in temperature chamber, and allowed to reach ambient temperature of about 37 degrees C.
  • a solution including Baclofen was then infused at a rate of about 1 milliliter/hour through the catheter 132.
  • Table I provides information pertaining to specific components of the apparatus 100 of Figure 7 used in these examples.
  • Figures 11 A-l 1C illustrate data collected with the pump 122 and cylinder 110 deactivated, e.g., no continuous or oscillatory flow.
  • Figures 12A-12C illustrate data collected when the pump 122 was set to deliver a continuous flow of about 12 milliliters/minute and the cylinder 110 was set to deliver an oscillating flow at about 1 Hz and at an amplitude that maintained the velocity of the fluid 108 at about 3 centimeters/second using the manual valve 120 and timer 121.
  • the X-axis on each graph of Figures 11 A- 11 C and 12 A- 12C represents the vertebral level at which the probes were placed.
  • the Y-axis shows relative drug concentration levels.
  • the magnitude of the Y-axis units are arbitrary and are derived from subsequent HPLC analysis.
  • Each line on the graphs of Figures 11A-11C and 12A-12C represents a different time point, each time point being about 30 minutes apart.
  • O' represents the start of infusion
  • '1' represents 30 minutes after the start of infusion
  • '2' represents 60 minutes following the start of infusion, etc.
  • Figures 11C and 12B include instances where one probe did not appear to be functioning properly, e.g., yielded zero concentration readings).
  • Apparatus and methods of the present invention thus permit both visual and quantitative modeling of substance, e.g., drug, distribution within the human spinal column.
  • the model apparatus may simulate not only the structural features of the human spine, but may also permit the simulation of various CSF flow characteristics present therein.
  • the complete disclosure of the patents, patent documents, and publications cited in the Background, the Detailed Description of Exemplary Embodiments, and elsewhere herein are incorporated by reference in their entirety as if each were individually incorporated. Exemplary embodiments of the present invention are described above. Those skilled in the art will recognize that many embodiments are possible within the scope of the invention. Other variations, modifications, and combinations of the various components and methods described herein can certainly be made and still fall within the scope of the invention. For example, other sampling methodologies may be combined with any of the spinal models described herein. Thus, the invention is limited only by the following claims, and equivalents thereto.

Landscapes

  • Engineering & Computer Science (AREA)
  • Physics & Mathematics (AREA)
  • General Physics & Mathematics (AREA)
  • Chemical & Material Sciences (AREA)
  • Computational Mathematics (AREA)
  • Mathematical Optimization (AREA)
  • Medical Informatics (AREA)
  • Medicinal Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Algebra (AREA)
  • Theoretical Computer Science (AREA)
  • Educational Technology (AREA)
  • Mathematical Analysis (AREA)
  • General Health & Medical Sciences (AREA)
  • Mathematical Physics (AREA)
  • Pure & Applied Mathematics (AREA)
  • Business, Economics & Management (AREA)
  • Educational Administration (AREA)
  • Manufacturing & Machinery (AREA)
  • Materials Engineering (AREA)
  • Infusion, Injection, And Reservoir Apparatuses (AREA)
  • Instructional Devices (AREA)

Abstract

L'invention concerne un appareil modèle in vitro de colonne vertébrale humaine et des procédés pour détecter et analyser des modèles de répartition de substances à l'intérieur de cet appareil. Dans un mode de réalisation, l'appareil modèle comprend un élément colonne définissant un passage qui ressemble sensiblement par sa taille, sa forme et sa structure à un canal spinal humain adulte. Une structure de corde est également placée et ancrée à l'intérieur du passage, cette structure de corde ressemblant sensiblement par sa taille, sa forme et sa structure à une moelle épinière d'humain adulte. Par exemple, la structure de corde peut comporter des éléments de liaison qui ressemblent à des racines nerveuses, à des ligaments dentés et au septum posticum de colonne vertébrale humaine. Le passage de l'appareil modèle peut être rempli d'un premier fluide qui simule le fluide céphalo-rachidien (CSF), un second fluide contenant un médicament (ou un médicament factice) pouvant être introduit dans ledit passage, la répartition du médicament à l'intérieur du passage pouvant alors être analysée.
PCT/US2004/032642 2003-10-03 2004-10-01 Modeles de colonne vertebrale tridimensionnels in vitro et procedes pour analyser la repartition d'une substance dans ces modeles WO2005036502A2 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US50835303P 2003-10-03 2003-10-03
US60/508,353 2003-10-03
US53241403P 2003-12-23 2003-12-23
US60/532,414 2003-12-23
US56686604P 2004-04-30 2004-04-30
US60/566,866 2004-04-30

Publications (2)

Publication Number Publication Date
WO2005036502A2 true WO2005036502A2 (fr) 2005-04-21
WO2005036502A3 WO2005036502A3 (fr) 2005-09-22

Family

ID=34437664

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2004/032642 WO2005036502A2 (fr) 2003-10-03 2004-10-01 Modeles de colonne vertebrale tridimensionnels in vitro et procedes pour analyser la repartition d'une substance dans ces modeles

Country Status (2)

Country Link
US (1) US7403883B2 (fr)
WO (1) WO2005036502A2 (fr)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7632100B2 (en) * 2004-09-03 2009-12-15 Birth Injury Prevention, Llc Brachial plexus simulator
US8137110B2 (en) * 2005-02-03 2012-03-20 Christopher Sakezles Dielectric properties models and methods of using same
US7824184B2 (en) * 2006-01-13 2010-11-02 Mts Systems Corporation Integrated central manifold for orthopedic simulator
EP1977200A4 (fr) * 2006-01-13 2014-04-09 Mts System Corp Chargement de facteur d'utilisation pour simulateur orthopédique
US8113847B2 (en) * 2007-10-23 2012-02-14 K2M, Inc. Spinal surgery modeling system
GB201107691D0 (en) * 2011-05-09 2011-06-22 Univ St Andrews Spinal phantom and spinal navigation
US8801438B2 (en) 2011-11-23 2014-08-12 Christopher Sakezles Artificial anatomic model
GB201217768D0 (en) * 2012-10-04 2012-11-14 Univ Bath Methods and apparatus for the in vitro modelling of subcutaneous injection
US9011158B2 (en) * 2013-02-07 2015-04-21 The Johns Hopkins University Human surrogate neck model
US10002546B2 (en) 2013-07-18 2018-06-19 Biotras Holdings, Llc Spinal injection trainer and methods therefor
US9280915B1 (en) 2013-07-18 2016-03-08 Biotras Llc Spinal injection trainer and methods therefor
US9378661B2 (en) 2013-07-18 2016-06-28 Biotras Llc Spinal injection trainer and methods therefor
US10255829B2 (en) 2016-10-10 2019-04-09 Medtronic Holding Company Sàrl In-situ training apparatus, method and system
US10102776B2 (en) * 2016-11-17 2018-10-16 Warsaw Orthopedic, Inc. Simulation device and method for using same
TR201722966A2 (tr) * 2017-12-29 2019-07-22 Mustafa Ilhan Goekler Boyun i̇nci̇nmeleri̇ni̇n i̇ncelenebi̇leceği̇ bi̇r boyun modeli̇
US11417241B2 (en) 2018-12-01 2022-08-16 Syndaver Labs, Inc. Artificial canine model
KR102325876B1 (ko) 2019-12-05 2021-11-12 차의과학대학교 산학협력단 신경에 대한 효능 및 독성평가를 위한 생체모방 신경칩 및 이의 용도
BR102019026105B1 (pt) * 2019-12-10 2023-12-05 Cristália Produtos Químicos Farmacêuticos Ltda Modelo simulador para anestesias

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2207153A (en) * 1939-04-07 1940-07-09 Bernard D Judovich Electric nerve injection model of the spine
FR2776805A1 (fr) * 1998-03-30 1999-10-01 Eurosurgical Structure anatomique pour la formation de chirurgiens a la chirurgie orthopedique, notamment rachidienne
GB2369714A (en) * 2000-11-28 2002-06-05 John Edward Duggan An epidural simulator device.

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3724467A (en) * 1971-04-23 1973-04-03 Avery Labor Inc Electrode implant for the neuro-stimulation of the spinal cord
US4773865A (en) * 1987-06-26 1988-09-27 Baldwin Jere F Training mannequin
GB8826967D0 (en) * 1988-11-18 1988-12-21 Secr Defence Anthropomorphic dummies
US5501703A (en) * 1994-01-24 1996-03-26 Medtronic, Inc. Multichannel apparatus for epidural spinal cord stimulator
US5672059A (en) * 1995-03-20 1997-09-30 Browne-Wilkinson; Oliver Orthopaedic human skeletal demonstration aids
US6319241B1 (en) * 1998-04-30 2001-11-20 Medtronic, Inc. Techniques for positioning therapy delivery elements within a spinal cord or a brain
US6422874B1 (en) * 2000-10-12 2002-07-23 Ronald Green Vertebral model
US20030083299A1 (en) * 2000-11-04 2003-05-01 Ferguson Ian A. Non-invasive delivery of polypeptides through the blood-brain barrier
JP2004533297A (ja) * 2001-05-29 2004-11-04 メドトロニック・インコーポレーテッド 心臓病の予防及び処置のための閉ループ神経調節システム
US6908309B2 (en) * 2001-12-03 2005-06-21 Sdgi Holdings, Inc. Demonstration devices for medical procedures
US20040101815A1 (en) * 2002-11-27 2004-05-27 Jay Mark A. Biofidelic seating apparatus with binaural acoustical sensing
US20040203079A1 (en) * 2003-04-09 2004-10-14 Research Foundation Of The State University Of New York Methods and kits for detecting cerebrospinal fluid in a sample

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2207153A (en) * 1939-04-07 1940-07-09 Bernard D Judovich Electric nerve injection model of the spine
FR2776805A1 (fr) * 1998-03-30 1999-10-01 Eurosurgical Structure anatomique pour la formation de chirurgiens a la chirurgie orthopedique, notamment rachidienne
GB2369714A (en) * 2000-11-28 2002-06-05 John Edward Duggan An epidural simulator device.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WACHTER DE D S ET AL: "DISTRIBUTION OF MARCAINE IN AN IN VITRO MODEL OF THE SUBARACHNOID SPACE CONFORMING TO ACTUAL SPINAL COLUMN GEOMETRIES" TECHNOLOGY AND HEALTH CARE, IOS PRESS, AMSTERDAM,, NL, vol. 5, no. 6, December 1997 (1997-12), pages 437-447, XP008045738 ISSN: 0928-7329 *

Also Published As

Publication number Publication date
US7403883B2 (en) 2008-07-22
WO2005036502A3 (fr) 2005-09-22
US20050106545A1 (en) 2005-05-19

Similar Documents

Publication Publication Date Title
US7403883B2 (en) Three-dimensional in-vitro spinal models and methods of analyzing substance distribution therein
Madihally Principles of biomedical engineering
Klarica et al. The movement of cerebrospinal fluid and its relationship with substances behavior in cerebrospinal and interstitial fluid
Linninger et al. Cerebrospinal fluid flow in the normal and hydrocephalic human brain
US20200256943A1 (en) Mri phantom including hollow fluid filled tubular textiles for calibrated anisotropic imaging
ES2533530T3 (es) Dispositivo para medir y regular parámetros del líquido cefalorraquídeo
KR20210027416A (ko) 자기 공명 영상과 호환 가능한 대류 강화 전달 두개골 임플란트 장치 및 관련 방법
US20090024181A1 (en) Treatment simulator for brain diseases and method of use thereof
EP3831281A1 (fr) Procédés de ciblage et d'administration biomédicaux, et dispositifs et systèmes pour leur mise en uvre
Sachs et al. Studies on cerebrospinal circulation by a new method
Rao Electrical impedance tomography of brain activity: studies into its accuracy and physiological mechanisms
Mertens et al. Microdialysis study of amino acid neurotransmitters in the spinal dorsal horn of patients undergoing microsurgical dorsal root entry zone lesioning
Bulat et al. Neurochemical study of the cerebrospinal fluid
Balasundaram et al. Hydrocephalic cerebrospinal fluid flowing rotationally with pulsatile boundaries: a mathematical simulation of the thermodynamical approach
WO2021214323A1 (fr) Système d'imitation médicale
Tangen et al. Cerebrospinal fluid dynamics and intrathecal delivery
Isherwood et al. Computer Tomography of the Spine: A Preliminary Report
Bilger Patient-specific biomechanical simulation for deep brain stimulation
Ayansiji Drug Delivery to the Central Nervous Syatem
Kedarasetti Drivers of Fluid and Metabolite Transport in the Central Nervous System
Samaranch et al. Cerebellomedullary cistern injection of viral vectors in nonhuman primates
RU2532878C1 (ru) Способ моделирования и изучения внутрибрюшного давления
DE102020202272B3 (de) Reanimationsphantom
Bortolussi Computational modeling of flow in the kidney
US11058510B2 (en) Spine-mounted stereotactic systems and related methods

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase